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MH Vickers, S Reddy, BA Ikenasio and BH Breier

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells. We therefore investigated the relationship between circulating plasma concentrations of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were programmed to become obese during adult life. Virgin Wistar rats were time mated and randomly assigned to receive food either available ad libitum (AD group) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6.13+/-0.04 g, UN 4.02+/-0.03 g, P<0.001). At weaning, offspring were assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P<0.005) fasting plasma insulin (AD control 1.417+/-0.15 ng/ml, UN control 2.493+/-0.33 ng/ml, AD hypercaloric 1.70+/-0.17 ng/ml, UN hypercaloric 2.608+/-0.41 ng/ml) and leptin (AD control 8.8+/-1.6 ng/ml, UN control 14.32+/-1.9 ng/ml, AD hypercaloric 15.11+/-1.8 ng/ml, UN hypercaloric 30.18+/-5.3 ng/ml) concentrations, which were further increased (P<0.05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeling for leptin in the peripheral cells of the pancreatic islets. Dual immunofluorescence histochemistry for somatostatin and leptin revealed that leptin was co-localized in the pancreatic delta-cells. OB-R immunoreactivity was evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.

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Steve O'Rahilly

leptin 20 years ago, Jeff Friedman has contributed a personal piece reflecting on the process of leptin's discovery and adumbrating the questions that remain ( Friedman 2014 ). The identification of the leptin receptor ( Tartaglia et al . 1995 ) and its

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ZA Archer, SM Rhind, PA Findlay, CE Kyle, L Thomas, M Marie and CL Adam

Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.

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Candida N Perera, Hwei G Chin, Nadire Duru and Ignacio G Camarillo

Leptin and connective tissue growth factor in advanced glycation end-product-induced effects in NRK-49F cells . Journal of Cellular Biochemistry 93 940 – 950 . Nakatsuji T 2006 Rat thymectomy effects on leptin receptor and T-bet: erythroid

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Sara Yosefi, Gideon Hen, Charles I Rosenblum, David J Cerasale, Michaël Beaulieu, Francois Criscuolo and Miriam Friedman-Einat

fat stores to the hypothalamus and peripheral tissues, which then modulate their activity according to energy status. The more recent identification of leptin and leptin receptor (LEPR) in non-mammalian vertebrates, such as fish ( Johnson et al . 2000

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A F Roy, Y Benomar, V Bailleux, C M Vacher, A Aubourg, A Gertler, J Djiane and M Taouis

study, we focused mainly on PRL and leptin. These cytokines share a number of signaling pathways acting through cytokine class I receptors. Long isoforms of PRL and leptin receptors (ObRb) act respectively through JAK-2/STAT-5 and JAK-2/STAT-3 signaling

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Martha Lappas, Kirin Yee, Michael Permezel and Gregory E Rice

villous vascular endothelial cells, which are in direct contact with the fetal blood ( Lea et al. 2000 ). Both long and short leptin receptor (Ob-R) isoforms are present in placenta, and are co-localized with leptin to the syncytiotrophoblast at the

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Sharon H Chou and Christos Mantzoros

neurons to secrete kisspeptins that then stimulate gonadotropin-releasing hormone (GnRH) neurons ( Sanchez-Garrido & Tena-Sempere 2013 ); leptin itself cannot stimulate GnRH neurons as they do not express leptin receptors ( Quennell et al . 2009

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Abdoulaye Diane, Maria Kupreeva, Faye Borthwick, Spencer D Proctor, W David Pierce and Donna F Vine

, Quennell et al . 2011 ). Hypothalamic nuclei expressing the leptin receptor produce different neuropeptides (proopiomelanocortin (POMC), neuropeptide Y (NPY), cocaine-and amphetamine-regulated transcript (CART), Kisspeptin) and peptides such as mammalian

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Christian K Tipsmark, Christina N Strom, Sean T Bailey and Russell J Borski

tissues including liver and adipose ( Kurokawa et al . 2005 , Huising et al . 2006 a ). Leptin receptors are also present in the genome of teleosts examined thus far ( Huising et al . 2006 b ). Since its discovery, the biology of leptin has been